Enhanced cytotoxicity and altered biglycan synthesis in vascular endothelial cells by cadmium through induction of CHSY1 expression

Abstract

Cadmium is an environmental pollutant and risk factor for atherosclerosis. In the atherosclerotic intima, dermatan sulfate chains accumulate and accelerate the oxidation of LDL cholesterol. Biglycan is the major dermatan sulfate proteoglycan synthesized and secreted by vascular endothelial cells. The purpose of this study is to investigate the effect of cadmium on the synthesis of biglycan in vascular endothelial cells. Confluent cultures of vascular endothelial cells were exposed to cadmium with or without of [³H]glucosamine and [³⁵S]sulfate. Proteoglycans extracted from the cell layer and conditioned medium were separated by anion exchange chromatography. The radioactivity of [³H]glucosamine was increased in biglycan-containing peak but that of [³⁵S]sulfate was not affected by cadmium. The fractions of this peak from the conditioned medium were collected and further analyzed by size exclusion chromatography. Cadmium elongated the length of dermatan sulfate chains and upregulated the expression of CHSY1, an elongation enzyme of dermatan sulfate chains, mediated by protein kinase C, while cadmium did not affect the expression of biglycan mRNA and core protein expression. In addition, CHSY1 overexpression increased the leakage of lactate dehydrogenase by cadmium from vascular endothelial cells. These results suggest that cadmium-induced CHSY1 contributes to the progression of atherosclerosis by not only elongating the dermatan sulfate chains of biglycan but also exacerbating the cytotoxicity of cadmium.